The proposed project is designed to continue a systematic investigation of the neural mechanisms of body weight regulation and feeding. The present investigator has reported that lesions of the lateral hypothalamus chronically lower the level at which an animal regulates its body weight. Since lesions of the ventromedial hypothalamus also produce a weight regulation adjustment--an elevated weight level--our results led us to propose a body weight set-point analysis of the two hypothalamic feeding syndromes. Additional research has supported the finding that the hypothalamic feeding mechanisms are involved in the control of body weight. Our recent experiments also suggest that the body weight changes and concomitant patterns of metabolism and food intake associated with the hypothalamic disturbances may reflect alterations in the autonomic control of digestion and metabolism. Put broadly, the aims of the research proposed in this application are (1) to characterize more fully the role of the vagus nerve in the ventromedial syndrome, (2) to determine more completely the autonomic and endocrine components of the lateral hypothalamic weight syndrome, (3) to explore the physiology and anatomy of the vagus nerve in greater detail, (4) to evaluate the presently available explanations of our results with autonomic manipulations and the hypothalamic feeding syndromes, and (5) to identify neural, neuroendocrine, and behavioral pathways involved in several mouse models of obesity. To these ends, a battery of surgical, anatomical, physiological, and behavioral strategies will be employed. The proposed grant, then, will increase our understanding of the role(s) of the hypothalamus and the autonomic nervous system in controlling metabolism and food intake and will fill an important gap in our knowledge of the pathways involved in obesity and weight regulations.